Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)

INTRODUCTION — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).

There are a number of inborn errors of glycogen metabolism that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.

Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.

●The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

●Glycogen serves as the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.

Lysosome-associated membrane protein 2 (LAMP2) deficiency (GSD IIb, MIM 300257) [1] is known as Danon disease, predominantly affects cardiac and skeletal muscle, and also includes neurologic manifestations. It has also been called lysosomal GSD with normal acid maltase (acid maltase deficiency is GSD II).

This topic will review LAMP2 deficiency (GSD IIb). An overview of glycogen storage disease is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

GENETICS — GSD IIb is an X-linked dominant disorder. It is due to pathogenic variants in the gene encoding lysosome-associated membrane protein 2 (LAMP2), located at Xq24. The specific function of LAMP2 is poorly understood, but three isoforms arising from the same gene are recognized, and the glycoprotein is involved in lysosomal enzyme targeting, autophagy, and lysosomal biogenesis [2,3]. LAMP2 also plays a critical role in lysosomal cholesterol and triglyceride metabolism [4]. A number of point mutations or small deletions or insertions within the LAMP2 gene and also splicing mutations have been identified [5-11]. Females are typically less affected than males. Intrafamilial variability of the Danon disease phenotype was reported in one family in which the mother and her three sons were affected [12].

CLINICAL FEATURES — Danon disease is characterized by severe cardiomyopathy, mild skeletal myopathy, ophthalmic abnormalities, and variable intellectual disabilities and psychiatric symptoms [13-17]. The age of onset ranges from infancy to adulthood. Female carriers typically have a later onset of disease [14,18] and exhibit a lower incidence of intellectual disabilities [19]. The cardiomyopathy may be the presenting manifestation, typically hypertrophic in form, but may also be dilated, and cardiac arrhythmias due in part to progressive fibrosis are a prominent cause of sudden death [14,15].

The clinical features of Danon disease were described in 38 affected patients in 13 families with genetically confirmed disease. All had cardiomyopathy [14]. Skeletal myopathy occurred in 18 of 20 males and 6 of 18 females. Intellectual disabilities were present in 14 males and 1 female. Other reports describe higher rates of intellectual disabilities in females [19]. Late-onset disease with onset in the fifth decade or later, characterized by mild cardiac phenotype with progressive generalized severe skeletal muscle weakness without intellectual disability, has been described in male members of a family with a novel missense mutation in the LAMP2 gene [20]. LAMP2 protein staining in the skeletal muscle was normal.

The natural history of Danon disease was reviewed in a series of 82 patients from 36 families [21]. Males were more severely affected, with high rates of cognitive disabilities (100 percent), hypertrophic cardiomyopathy (88 percent), and muscle weakness (80 percent). The average age of first cardiac symptoms was 12 years. In addition, they had a higher rate of mortality and were unlikely to reach the age of 25 years without cardiac transplantation. Females were less severely affected and presented approximately 15 years later than males but had higher than expected rates of cognitive disability (47 percent) and skeletal muscle complaints (50 percent). Conduction abnormalities were reported in more than three-quarters of patients.

Ophthalmic manifestations were described in another series of six patients, including four females and two males [22]. All of the females had peripheral retinal pigmentary changes ("peppered" or "mottled"), whereas the males had near-complete loss of retinal pigment. Additional findings included lens changes, myopia, and abnormal electroretinogram and visual fields.

Danon disease may be an underrecognized cause of hypertrophic cardiomyopathy in childhood and early adulthood. The cardiomyopathy usually develops before age 20 years in males and in adulthood in females. As an example, an asymptomatic 19-year-old male patient with left ventricular hypertrophy, but without intellectual disability or significant skeletal myopathy, was found to have Danon disease [23]. However, hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, and intellectual disability were described in a 12-year-old female with Danon disease, demonstrating that these features are sometimes also seen in young females [16]. An accurate diagnosis is important for instituting an appropriate treatment plan and for genetic counseling. Cardiomyopathy in patients with Danon disease is discussed separately. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'PRKAG2 and LAMP2 genes'.)

In addition to hypertrophic cardiomyopathy, dilated cardiomyopathy has also been described in several patients [24,25].

DIAGNOSIS — Creatine kinase (CPK) typically is moderately elevated. The diagnosis is suggested by muscle biopsy. The characteristic pathologic feature is intracytoplasmic vacuoles that contain autophagic material and glycogen in skeletal muscle cells, although, in young children, the vacuoles may not yet be present [24]. The vacuoles are also present in cardiac tissue. Acid phosphatase-positive material is present within membranes that lack LAMP2 [14]. Acid alpha glucosidase activity is normal. LAMP2 staining is sometimes absent in skeletal muscle but not always [20]. The detection of a mutation in the LAMP2 gene confirms the diagnosis.

Another condition with progressive proximal muscle weakness and similar muscle biopsy findings and probably pathogenesis is X-linked recessive myopathy with excessive autophagy (XMEA) due to vacuolar ATPase assembly factor VMA21 (VMA21) pathogenic variants. In XMEA, however, there is lack of cardiac, ocular, and cognitive involvement [26].

A flow cytometry assay for LAMP2 protein expression is under study to detect carriers of LAMP2 deficiency [27]. Lack of symptoms in female carriers may be due to mosaicism, suggesting that carriers may be underdiagnosed. Flow cytometry for LAMP2 may be an efficient method for screening of family members of an affected patient [28,29].

TREATMENT — No specific treatment is available for the disorder. Cardiac transplantation is the most effective treatment for the cardiomyopathy and has been performed in both males and females [14,18,30]. A survey of 38 transplanted patients from eight centers (19 males and 19 females) demonstrated that the median age of transplant was 20 years in males and in females, with an estimated five-year survival of 87 percent [31]. In this cohort, extracardiac manifestations such as intellectual disabilities and psychiatric symptoms were similarly equally present in males and females, with the latter reported in 50 percent of all patients, perhaps reflecting the severe morbidity of the cohort. However, a high frequency of psychiatric diagnoses has been reported in other cohorts [32].

SUMMARY

●Lysosome-associated membrane protein 2 (LAMP2) deficiency (glycogen storage disease [GSD] IIb, Danon disease) is an X-linked disorder due to pathogenic variants in the gene encoding LAMP2. The specific function of LAMP2 is poorly understood. (See 'Genetics' above.)

●LAMP2 deficiency is usually characterized by severe cardiomyopathy, mild skeletal myopathy, ophthalmologic abnormalities, and variable intellectual disability. The age of onset ranges from infancy to adulthood. Female carriers usually have a later onset of disease. Males with severe skeletal myopathy and mild cardiac involvement, and vice versa, have also been described. (See 'Clinical features' above.)

●Laboratory features of LAMP2 deficiency include moderately elevated creatine kinase (CPK). The diagnosis is supported by muscle biopsy demonstrating intracytoplasmic vacuoles that contain autophagic material and glycogen. DNA testing is commercially available. (See 'Diagnosis' above.)

●No specific treatment is available, but early consideration of heart transplantation may be lifesaving. (See 'Treatment' above.)