Glycogen storage disease type IV
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vellayat Ali M.B.B.S[2]
Synonyms and keywords: Andersen Disease; Brancher deficiency; Amylopectinosis; Glycogen Branching Enzyme Deficiency; Glycogenosis IV; Adult polyglucosan body disease (APBD)
Overview
Historical Perspective
- In 1952, B Illingworth and GT Cori observed accumulation of an abnormal glycogen (resembling amylopectin) in the liver of a patient with von Gierke’s Disease. They postulated this finding to a different type of enzymatic deficiency, and thus to a different type of glycogen storage disease.[1]
- In 1956, DH Andersen, an American pathologist and pediatrician, reported the first clinical case of the disease as "familial cirrhosis of the liver with storage of abnormal glycogen".[2]
- In 1966, BI Brown and DH Brown clearly demonstrated the deficiency of glycogen branching enzyme (alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase) in a case of Type IV glycogenosis.[3]
Classification
There is no established system for the classification of GSD Type IV. The deficiency of GBE affecting liver, brain, heart, and skeletal muscles leads to variable clinical presentations. Based on organ/tissue involvement, age of onset and clinical features, Andersen disease can be segregated into various forms [16] as below:
Form of Presentation | Age of
Onset |
Clinical Features | |
---|---|---|---|
Classic Hepatic Form | 0-18 mo | Infants with classic hepatic form present with failure to thrive, hypotonia and hepatosplenomegaly. The disease progresses to portal hypertension, ascites, and liver failure, leading to death by 5 years of age.[17]. | |
Neuro-
Musuclar Form |
Perinatal | In utero | Prenatal symptoms include, polyhydramnios, hydrops fetalis, and decreased fetal movement; at birth severe hypotonia is observed requiring mechanical ventilation for respiratory support. [18][19] Cardiac findings like progressive cardiomyopathy may also be present.[19] |
Congenital | At birth | Newborns may present with severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration and neuronal involvement, leading to death in early infancy.[21] | |
Late childhood | 0-18 yrs | Presents in childhood at any age with myopathy as exercise intolerance, and cardiopathy as exertional dyspnea; and congestive heart failure in progressed cases. [21]. | |
Adult | >18-21 yrs (any age in adulthood) | May present as isolated myopathy [23] or as Adult Polyglucosan Body Disease (APBD) [22] |
Adult Polyglucosan Body Disease (APBD)
- Adult Polyglucosan body disease is one of the neuromuscular variant of GSD Type IV.
- Typically, the first clinical manifestation is of urinary incontinence secondary to neurogenic bladder. [15]
- This is followed by gait disturbance (due to spastic paraplegia) and lower limb paresthesias. [15]
- Patients deteriorate slowly over years and lose ability to ambulate independently, and develop paralysis of the upper limbs as well. [24]
- Progressive dementia is also seen in these patients.[25]
- The disease often leads to premature death.[15]
Pathophysiology
Pathogenesis
- Glycogen storage disease type IV is an autosomal recessive genetic disorder which results due to deficiency of glycogen branching enzyme (GBE).[4]
- During Glycogenesis, the branching enzyme introduces branches to growing glycogen chains by transferring α-1,4-linked glucose monomers from the outer end of a chain into an α-1,6 position of the same or neighboring glycogen chain. [6]
- Deficiency of GBE affects the branching process, yielding a polysaccharide which has fewer branching points and longer outer chains, thus resembling amylopectin. This new amylopectin-like structure is also known as polyglucosan. [7]
- The enzyme deficiency affects all the bodily tissues; but liver, heart, skeletal muscles, and the nervous system are mostly affected.
- The abnormally branched glycogen accumulates as intracytoplasmic non membrane-bound inclusions in hepatocytes, myocytes, and neuromuscular system; where it increases osmotic pressure within cells, causing cellular swelling and death.[8][9]
- The altered structure also renders glycogen to become less soluble, and this is thought to lead into a foreign body reaction causing fibrosis, and finally culminating in liver failure. [10][11]
- In skeletal muscle, accumulation leads to muscle weakness, fatigue, exercise intolerance, and muscular atrophy. [12]
- The heart may be affected with a wide spectrum of cardiomyopathy; from dilated to hypertrophic and from asymptomatic to decompensated heart failure may occur. [13]
- Although exact mechanism for this pathology is not known, glycogen deposition in the myocardium is thought to initiate signaling pathways which cause sarcomeric hypertrophy, resulting in hypertrophic cardiomyopathy.[14]
Genetics
- Glycogen branching enzyme is a 702 amino acid protein encoded by GBE1 gene mapped to chromosome 3p12.2. HUGO Gene Nomenclature Committee https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:4180 The Universal Protein Resource (UniProt) http://www.uniprot.org/uniprot/Q04446
- Mutations in the GBE1 are responsible for enzymatic deficiency, and so far 40 pathogenic variants have been identified in individuals with GSD IV or adult-onset polyglucosan body disease (APBD).PMID: 23285490
Causes
- The cause of GSD type IV is variable deficiency of glycogen branching enzyme (GBE).
- The deficiency is due to various mutations of GBE1 gene encoding the single polypeptide protein.
Differentiating ((Page name)) from Other Diseases
- Comparisons may be useful for a differential diagnosis as a number of other disease conditions with clinical features may present similar to those associated with GSD Type IV.
- Presenting as hepatomegaly in infancy, the following glycogen metabolism disorders should be differentiated from GSD Type IV;
-GSD Type I
-GSD Type III
-GSD Type VI
-Hepatic Phosphorylase b Kinase Deficiency
- Metabolic disorders presenting with muscle weakness/myopathy during infancy should also be considered;
-Muscle glycogen synthase deficiency (GSD0b)
-Lysosomal acid maltase deficiency (GSD II)
-Glycogen debrancher deficiency (GSD III)
-Muscle phosphorylase deficiency (GSD V)
-Aldolase A deficiency (GSD XII)
-Glycogenin-1 deficiency (GSD XV)
Epidemiology and Demographics
FREQUENCY
- The frequency of all glycogen storage diseases is estimated to be 1 in 20,000 to 25,000 live births, while GSD IV is estimated to occur in 1 in 600,000 to 800,000 individuals worldwide. NORD GHR https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-iv#statistics
SEX
- Males and females appear to be affected in relatively equal numbers [NORD] because the deficiency of glycogen-branching enzyme activity is inherited as an autosomal-recessive trait.
RACE
- Familial aggregation is observed in about 30% of adult polyglucosan body disease cases, especially among Ashkenazi Jewish populations. NORD
Risk Factors
There are no established risk factors for [disease name].
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The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].
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Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
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Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.
Screening
There is insufficient evidence to recommend routine screening for [disease/malignancy].
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According to the [guideline name], screening for [disease name] is not recommended.
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According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].
Natural History, Complications, and Prognosis
If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
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Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
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Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.
Diagnosis
- Glycogen storage disease type IV should be suspected in a patient based on clinical features and finding abnormally branched glycogen accumulation in muscle or liver tissue.
Diagnostic Study of Choice
- The diagnosis is confirmed by demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts [PMID: 6220706], and/or
- Molecular genetic testing of GBE1 gene for mutations https://www.ncbi.nlm.nih.gov/books/NBK115333/
History and Symptoms
· Classically, the patient presents in their first year of life with complaints of failure to thrive and hepatosplenomegaly.[17]
· As the disease progress towards cirrhosis, features of hepatic failure become evident.
· Rarely in some children, hepatomegaly is the only presentation and disease does not progress to liver failure. PubMed: 8830177 [PubMed: 3162725]
· In perinatal variant, affected newborns may have a prenatal history of polyhydramnios, reduced utero fetal movements and fetal hydrops. At birth, lack of active movements, sucking, and swallowing is noted. PMID 15669676
· Individuals with late childhood form usually present in the second decade of life with complaints of exercise intolerance and exertional dyspnea secondary to muscle involvement and cardiomyopathy respectively.[20] [21]
Physical Examination
Findings on physical examination of patients with glycogen storage disease type IV vary with respect to the disease variant and organ system involved.
In infants with the classic (hepatic) form of GSD type IV, findings depicting liver involvement predominate:
· Abdominal protuberance
· Hepatosplenomegaly [17]
· Signs and symptoms of portal hypertension [17]
Newborns with perinatal form of disease may show:
· Poor respiratory effort at birth [7]
· Hyporeflexia [PubMed: 15452297]
· Severely decreased muscle tone [PubMed: 4502299] [PubMed: 8059607]
Patients with ‘late childhood form’ of disease may have:
· dysmorphic features [PubMed: 7683169]
· myopathic faces, hypotonia, and waddling gait with hyperlordosis [PubMed: 15452297]
Laboratory Findings
- Liver functions tests:
- ALT and AST are typically elevated in the hepatic subtype of disease.https://www.ncbi.nlm.nih.gov/books/NBK115333/#gsd4.Diagnosis
- Decreased albumin levels, prolonged partial thromboplastin time (PTT) and prothrombin time (PT) are seen with progressive liver dysfunction. https://www.ncbi.nlm.nih.gov/books/NBK115333/#gsd4.Diagnosis
- GBE activity
- Decreased activity of glycogen branching enzyme can usually be shown in the liver, leukocytes, erythrocytes and fibroblasts [PMID:11949934] PMID:2972882
- Creatinine Kinase levels:
- CK levels are usually elevated, demonstrating muscle pathology, in the neuromuscular forms of the disease.
- Liver biopsy
- Liver biopsy shows accumulation of abnormal glycogen in hepatocytes. PMID:1067751
- The deposits appear precipitated and are centrally placed in the hepatocytes, while nuclei are eccentric in position. PMID:1067751
- The deposits stain strongly positive with periodic acid-Schiff (PAS), appear brown with iodine, and are only partially digested by diastase. PMID:1067751
- Chitotriosidase levels:
- Plasma chitotriosidase levels are noted to be elevated in GSD Type IV. PMID: 15669690
X-ray
There are no x-ray findings associated with [disease name].
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An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
Electrocardiogram
There are no ECG findings associated with [disease name].
OR
An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
Echocardiography
- In patients with symptoms of heart failure, echocardiography may show evidence of cardiomyopathy. PMID:20833045
Ultrasonography
- Abdominal ultrasound examination shows hepatosplenomegaly and coarse echo pattern of the liver.
CT scan
There are no CT scan findings associated with [disease name].
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[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].
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There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].
MRI
MRI of the head may reveal leukoencephaly and cortical atrophy in patients with adult polyglucosan body disease (APBD) and CNS involvement. MRI typically demonstrates medullary and spinal atrophy, mild thinning of corpus callosum, and symmetric periventricular white matter changes with occipital predominance
Treatment
Medical Therapy
There is no treatment for [disease name]; the mainstay of therapy is supportive care.
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Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].
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The majority of cases of [disease name] are self-limited and require only supportive care.
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[Disease name] is a medical emergency and requires prompt treatment.
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The mainstay of treatment for [disease name] is [therapy].
OR The optimal therapy for [malignancy name] depends on the stage at diagnosis.
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[Therapy] is recommended among all patients who develop [disease name].
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Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].
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Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].
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Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].
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Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].
Surgery
Surgical intervention is not recommended for the management of [disease name].
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Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]
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The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].
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The feasibility of surgery depends on the stage of [malignancy] at diagnosis.
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Surgery is the mainstay of treatment for [disease or malignancy].